The hypothesis that coronary vasospasm can be due to hyperactivity per se was explored in rhesus monkeys (Macaca mulatta) in the absence of injury or significant vascular disease. We studied the vasoconstrictors reported to induce vasospasm in human patients. To determine whether endogenous chemical vasospasm stimuli are capable of directly inducing vasospasm, we used intracoronary (IC) injections of serotonin, thromboxane A2 (as U46619), endothelin 1, or angiotensin II in concentrations 3 to 10 times the dose which reduced coronary artery diameter by 50%. Coronary artery catheterization studies of ovariectomized monkeys, with injection of vasospasm stimuli alone or in combination, showed the possibility for provoking vasospasm without endothelial denudation or injury. Although none of the agents alone caused vasospasm, the combination of pathophysiological concentrations of serotonin and the stable thromboxane A2 analog, U46619, injected via an IC catheter, synergistically caused coronary vasospasm on the 2nd or 3rd challenge in 5 of 7 monkeys. These iatrogenic coronary vasospasms in the rhesus monkey were very similar to vasospasms induced in other monkeys by mechanical injury followed by serotonin, and to those stimulated in human IC diagnostic catheterization tests, as judged by onset, appearance, kinetics, and vasodilator reversal. Successful vasospasm of non-atherosclerotic and uninjured primate coronary arteries in response to these 2 endogenous pathophysiological vasoconstrictors, which are thought to be the precipitating stimulus in the etiology of vasospasm, suggests that vasospastic (structure independent) epicardial vasospasm may be an important element in many vasospasms, and an explanation for focal, rapid onset constrictions which occur without plaques or injury.